Therapeutic gene transfer is considered as a promising novel strategy to treat genetic disorders and cancer. So far, target cells are often isolated from patients for this purpose, and re-administered after gene transfer. In collaboration with colleagues from the Universities of Cologne and Zurich, researchers at the Paul-Ehrlich-Institut have succeeded in developing gene transfer vehicles that target the therapy relevant cell type directly in the organism. The resulting gene transfer occurs with an extremely high degree of selectivity. A report on the research results can be found in Nature Communications in its online edition of 10.02.2015.

Vectors derived from adeno-associated viruses (AAV) were used as vehicles for targeted gene transfer by the research group of Professor Christian J. Buchholz, Principal Investigator at the LOEWE Centre for Cell and Gene Therapy at Frankfurt am Main and head of the Section “Molecular Biotechnology and Gene Therapy ” of the President of the Paul-Ehrlich-Institut.

AAV is a non-pathogenic parvovirus. The only gene therapy medicinal product authorised in Europe so far, is also based on AAV gene vectors and intended for the treatment of a rare metabolic disorder.

The strategy for the generation of the new precision gene vectors was developed and implemented jointly with Dr Hildegard Büning, head of the AAV Vector Development Research Group at the ZMMK (Zentrum für Molekulare Medizin Köln, Center for Molecular Medicine Cologne) of the University of Cologne: Through exchange of two amino acids, AAV lost its ability to bind to its natural receptor and became thereby unable to penetrate its broad range of natural target cells.

Novel target structures (DARPins, designed ankyrin repeat proteins) were then attached to the surface of the modified vector particles. These structures were developed at Zurich University. The structures can be selected in such a way that they mediate a selective binding of the DARPin-containing AAV vector particles to the therapy relevant cell type only.

This is what enables the AAV vector to attach to and penetrate the desired target cell. The paper referenced here reports on the use of three different DARPins, which equipped AAV vectors either with a specificity for Her2/neu, a tumour marker in breast cancer, for EpCAM, an epithelial surface protein, or for a marker of particular blood cells (CD4 on the surface of lymphocytes with distinct immunological functions).

In the mouse model, the vector for Her2/neu targeted 80 percent of all metastatic sites after only a single injection. If the vector was armed with a cytotoxic gene, the survival rate of the mice was substantially prolonged compared to mice receiving an authorised anti-tumour product. Using the EpCAM-targeted vector, tumour cells could be detected with impressive sensitivity in human blood (few hundred tumour cells in several millilitres of blood).

The desired goal of a cell type specific in vivo gene transfer was also achieved with the blood cell targeted vector: AAV transferred the gene only into lymphocytes present in spleen carrying the CD4 protein target structure.

“The method developed by us jointly is a very promising tool both in fundamental research and for the targeted gene transfer in medicine“, explained Dr Buchholz with regard to the current research results.

The Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines in Langen near Frankfurt/Main, is a senior federal authority reporting to the Federal Ministry of Health (Bundesministerium für Gesundheit, BMG). It is responsible for the research, assessment, and marketing authorisation of biomedicines for human use and veterinary vaccines. Its remit also includes the authorisation of clinical trials and pharmacovigilance, i.e. recording and evaluation of potential adverse effects. Other duties of the institute include official batch control, scientific advice and inspections. In-house experimental research in the field of biomedicines and life science form an indispensable basis for the varied and many tasks performed at the institute. The PEI, with its roughly 800 staff, also has advisory functions at a national level (federal government, federal states (Länder)), and at an international level (World Health Organisation, European Medicines Agency, European Commission, Council of Europe etc.).

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